(paraacyloxyphenoxy)-benzoic acid derivatives



United States Patent O This invention relates to novel derivatives of (p-acyloxyphenoxy)-benzoic acid and to the production of the same.

More particularly, the compounds of this invention are O-acyl derivatives of 3,5-diiodo-4-(3'-iodo-4'-hydroxyphenoxy)-benzoic acid.

It is well kown the thyroxine which is representable by the formula I I I I wherein R is --CH CH(NH )COOH is a thyroid hormone. And, it has recently been clarified that thyroxine can lower the blood cholesterol level of living bodies. This suggests the use of thyroxine for the treatment of arteriosclerosis. In spite of the presumption, thyroxine has not been actually used for the purpose, because there are many difiiculties on the synthetic route as the side chain of thyroxine is an amino acid moiety. Recently, however, it is further clarified that the amino acid moiety is not always necessarily present in the molecule for exhibiting the desired medicinal effect.

Namely, compounds having no amino acid moiety but carboxylic acid moiety show the desired efl'iciency so long as they have a similar skeleton to thyroxine. Thyroformic acid (I: R COOH), thyroacetic acid (I: R=CH COOH) and thyropropionic acid (I: R=CH CH COOH), for example, have also a similar medicinal eifect to that of thyroxine in lowering blood cholesterol level. But, these known compounds have such undesirable properties that they increase the basal metabolism and oxygen consumption. This is one of the undesirable effects of these compounds to' the patients suffering from arteriosclerosis. Of course, the most desirable compounds should be one which has a strong effect in lowering blood cholesterol level and does not show any action on the basal metabolism or oxygen consumption. G. S. Boyd and M. F. Oliver have investigated and compared these properties of variou compounds (Journal of Endocrinology, vol. 2l( 1960- 1961), pp. 25-43) for screening the most desirable compound among them.

In this invention 3,5-diiodo-4- (4'-hydroxy-3'-iodophenoxy) benzoic acid is acylated. The non-acylated compound has been reported in such journals as Biochemical Journal, vol. 21 (1927), p. 169, Journal of Biological Chemistry, vol. 179 (1949), p. 423, ibid., vol. 219 (1956), p. 595 and the Journal of the Chemical Society, 1951, p. 2472. The aforesaid comparative experiment by G. S. Boyd et a1. shows the good results of this compound in lowering blood cholesterol level. In spite of the good results, the compound still has the shortcoming that the lowered blood cholesterol level by this chemical can hardly 'be long-lasting.

On the other hand, the results of the present inventors investigation, have revealed that compounds of this invention have none of these deficiencies, although the compounds of this invention have closely related structure to the aforesaid known compounds. It is also interesting that 3,206,501 Patented Sept. 14, 1965 the O-acyl derivatives of 3,5-diiodo-4-'hydroxyphenoxy)- benzoic acid have far less action on lowering blood cholesterol level than the compound of this invention, which fact has been discovered also by the present inventor.

Thus, the object of this invention is to provide novel compounds which will effect a lower blood cholesterol level and maintain the lowered cholesterol level for a long time. Another object is to provide a method for the production of such compounds. These objects are realized by acylating 3,5-diiodo-4-'(3'iodo-4-hydroxyphenoxy)- benzoic acid.

The acyl group to be substituted for at the 4'-position of the starting material may, for example, be any of lower fatty acid acyl groups such as acetyl, propionyl and butyryl groups, monocyclic aromatic acyl groups such as benzoyl and toluyl groups and aralkyl carboxylic acid acyl groups such as benzyl carbonyl group. In the production of the compounds of this invention, 3,5-diiodo-4-(3'-iodo-4'-hydroxyphenoxy)-benzoic acid is acylated. The acylation may be conducted by action on the starting material of any of conventional acylating agents. The acylating agent may, for example, be an acid anhydride and acid halide corresponding respectively to the desired acyl group to be introduced. The action of these acylating agents on the starting material proceeds smoothly under heating with or without use of a suitable solvent. The solvent, if used, may be any inert solvent such as benzene, toluene, ether and petrolic solvent.

In case of employing the latter of the afore-exemplified two acylating agents on the starting material, a suitable basic material may preferably be used as a deacidating agent. As the basic material, any organic or inorganic "basic substances may be employed. For example, dialkylamine, pyridine, piperidine, alkali hydroxide, alkali carbonate and alkali alcoholate may be used for the purpose. Among these two kinds of acylating agent, the former is preferable. The iodine atom at the 3'-position is sometimes split off under a strong alkalinity.

The product has, in most cases especially where the acyl group is lower fatty acid acyl grou a strong resemblance to the starting material in its behavior, and therefore unreacted material is ditficult to remove if present. In general, the acylating agent is used in excess so that no unreacted material will remain, and the reaction is conducted until all of the starting material is change to the product. The end point of the reaction may be observed by utilizing a reagent from the phenolic hydroxyl group such as Paulys reagent, i.e. diazotized sulfanylic acid plus alkali. To isolate the product from the reaction mixture, first the excess of the acylating agent is removed, then crystallized. Recrystallization from a suitable solvent e.g. alcohol and ether gives a highly pure product.

The acute toxicity (LD of 3,5-diiodo-4-(3-iodo-4'- acetyloxyphenoxy)-benzoic acid to mice (strain CF male) is 3,000 to 4,000 milligrams per kilogram (per os) or 2,400 milligrams per kilogram (intrapertoneal injecttion). Other compounds of the present invention also show similar toxicities as the above. Thus, the compounds may safely be administered to living bodies either orally or by injection.

The compounds of this invention are useful for the treatment of various diseases caused from high cholesterol level such as atherosclerosis (cerebrosclerosis, cerebral vascular accident, encephalomalacia, senile dementia, arteriosclerotic parapathy, coronary arteriosclerosis, sclerosis of the aorta, hypertonia) and hypercholesteremia (essential hypercholesteremia) The compounds may generally be administered orally, but may be administered by injection if desired. When the administration is effected orally, the compounds may be in the form of tablets, granules, powder, internal solution, for instance. formulated with a suitable carrier or suitable carriers. The administration of the drug may be to 100 milligrams per day per patient as 3,5-diiodo-4- (3'-iodo-4'-acetyloxyphenoxy) benzoic acid. When the acyl group at the 4-position is other than acetyl group, the dose, of course, varies with their molecular weights.

By administration of this drug, the blood cholesterol level of a patient is lowered to a normal level, within 1 to 2 weeks after the start of administration. But, the cholesterol level can not be lowered below the normal level even when the administration is continued. For example, the total blood cholesterol level of 260 milligrams per deciliter found in a patient of arteriosclerosis (43 years old, female) was lowered to 180 milligrams per deciliter by the administration of 3,5-diiodo-4-(3-iodo-4'-acetyl oxyphenoxy)-benzoic acid (60 milligrams per day) for 100 days. Another patient (29 years old, female) sufiering from metabolic insufiiciency was given 90 milligrams per day of the same drug as above for days, so that the total blood cholesterol level of 260 milligrams per deciliter was lowered to 154 milligrams per deciliter. As a third example, a patient (56 years old, male) with essential hypertension was given 25 to 70 milligrams per day of the same drug as above for 80 days, the total blood cholesterol level of 270 milligrams per deciliter was lowered to 190 milligrams per deciliter.

. The administration of the compunds of this invention gives a parallel influence to blood phospholipids with total blood cholesterol level. Just after the start of administration of the drug, the basal metabolic ratio of the patient is slightly heightened, but the heightened ratio slowly drops until a normal ratio is reached. This shows the weak thyromimetic activity of the compounds of this invention.

No side effect has been observed in the administration of the compounds to patients during clinical examination. 7 The following examples are illustrative only and are not meant to limit or restrict the scope of the invention. In the examples, percent is by weight, and parts by weight and parts by volume bear the same relationship as gram per milliliter.

Example 1 A mixture of 3 parts by Weight of 3,5-diiodo-4-(3'-iodo- 4'-hydroxyphenoxy)-benzoic acid and 10 parts by weight of acetic anhydride is refluxed on an oil bath for a few hours until the reaction to a member from the phenolic hydroxyl group is negative. Then the excess acetic anhydride is removed completely under reduced pressure. After cooling, ether is added to the residue to give a White amorphous powder. Recrystallization of .the powder from glacial acetic acid gives 2.4 parts by weight of 3,5-diiodo- 4-(3'-iodo 4' acetyloxyphenoxy)-benzoic acid as small needles. M.P. 238 C.

' Analysis-Calcd. for C H O I C, 27.72%; H, 1.40%. Found C, 28.02%; H, 1.37%.

4 The product is slightly soluble in water, glacial acetic acid and ethyl alcohol, and easily soluble in acetone.

Example 2 A process similar to that of Example 1 is conducted employing either normal butyric anhydride or benzoic anhydride instead of acetic anhydride, whereby 3,5-diiodo- 4-(3-iodo-4' normal butyryloxyphenoxy)-benzoic acid (M.P. 225 C.) and 3,5-diiodo-4-(3'-iodo-4-benzoyloxyphenoxy)-benzoic acid (M.P. 148 C.) are obtained respectively. The analytical values of the products are in accord with the corresponding calculated values.

Having thus disclosed the invention, what is claimed is:

1.. O-acylv derivatives of 3.5-diiodo 4-(3-iodo-4-hydroxyphenoxy)-benzoic acid, wherein the acyl group is a member selected from the group consisting of lower alkanoyl having up to 4 carbon atoms, benzoyl, toluyl, and benzylcarbonyl.

2. Lower alkanoyl derivatives of 3,5-diiodo-4-(3-iodo- 4-hydroxyphenoxy)-benzoic acid the alkanoyl group having up to and including 4 carbon atoms.

3. 3,5-diiodo-4-(3-iodo-4' acetyloxyphenoxy)-benzoic acid.

4. 3.5-diiodo-4-(3' iodo-4' butyryloxyphenoxy)-benzoic acid.

5. 3,5-diiodo-4-(3'-iodo 4' benzoyloxyphenoxy)-benzoic acid.

References Cited by the Examiner UNITED STATES PATENTS 2,752,388 6/56 Dereska 260-479 2,913,484 11/59 Gordon 260-476 2,970,165 1/ 61 Michel et al. 260-473 2,978,381 4/61 Freedman 167-65 2,980,585 4/61 Stambul 167-65 OTHER REFERENCES Boyd et al.: Journal of Endocrinology, vol. 21 (1960- 61), pp. 2543.

' Bresciani et al.: Atti Accademia Nazional dei Lincer, Rendicanti classe di Scienze fisiche mat e nat., vol. 27, No. 2, pp. 255-8, 1959.

Clayton et al.: Journal of the Chemical Society (London) (1951), pp. 2467-2473.

Fisser et al.: Organic Chemistry, 3d edition, New York, Reinhold, 1956, pp. 174-176, 181-188 relied on.

. Frieden et al.: Journal of Bological Chemistry, vol. 179 1949 p. 423.

Tomita et al.: Journal of Biological Chemistry, vol. 219 (1956), p. 603.

LORRAINE A. WEINBERGER, Primary Examiner. DUVAL MCCUTCHEN, LEON ZITVER, Examiners. 

1. O-ACYL DERIVATIVES OF 3.5-DIIODO - 4-(3''-IODO-4''-HYDROXYPHENOXY)-BENZOIC ACID, WHEREIN THE ACYL GROUP IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF LOWER ALKANOYL AND HAVING UP TO 4 CARBON ATOMS, BENZOYL, TOLUYL, AND BENZYLCARBONYL. 